The aim of this proposal is to examine the factors controlling the release of gastric histamine in vivo in the dog. The overall hypothesis is that gastric mucosal histamine is regulated by gastric secretagogues, and the release is modulated by antisecretory polypeptides and autocoids. The dog is the correct model for these studies because dog gastric mucosal histology is similar to human gastric mucosal histology in that mast cells contain the bulk of the mucosal histamine. The proposed aim will be accomplished by measuring arterial and gastric venous plasma concentrations of histamine and 1-methyl histamine across the corpus of the stomach where most of the histamine-containing mast cells and endocrine cells are contained. By sampling blood from the gastric veins draining the corpus of the stomach and measuring gastric blood flow to the corpus of the stomach, histamine secretory rates can be calculated to various stimuli. In addition, methylhistamine measurements will allow the evaluation of histamine metabolism during prolonged infusion of secretagogues. By infusing compounds directly into the gastric artery supplying the corpus of the stomach, systemic effects of these compounds can be avoided. Histamine and methylhistamine will be measured by gas chromatography/negative ion chemical ionization mass spectrometry (GC/NICI-MS). Using this technique in preliminary experiments, we have demonstrated that pentagastrin infusion results in a large increase in histamine and methylhistamine release from the stomach. The proposal plans to examine the role of histamine release in pentagastrin-stimulated acid secretion will also be explored. And finally, antisecretory compounds will be examined for their ability to modulate histamine release. These compounds include antisecretory polypeptides somatostatin, glucagon, and secretin; antisecretory autocoids prostaglandins E2 and I2, and adenosine; sympathomimetic isoproterenol,and the histamine-2 agonist, dimaprit. These sets of experiments should generate new information about the control of gastric mucosal histamine release in the intact stomach. By understanding the physiologic and pharmacologic control of gastric mucosal histamine release, another pharmacology approach can be developed to control acid secretion in the treatment of peptic ulcer disease.